Sonographers' self-reported visualization of normal postmenopausal ovaries on transvaginal ultrasound is not reliable: results of expert review of archived images from UKCTOCS.

OBJECTIVE: In the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), self-reported visualization rate (VR) of the ovaries by the sonographer on annual transvaginal sonographic (TVS) examinations was a key quality control (QC) metric. The objective of this study was to assess self-reported VR using expert review of a random sample of archived images of TVS examinations from UKCTOCS, and then to develop software for measuring VR automatically. METHODS: A single expert reviewed images archived from 1000 TVS examinations selected randomly from 68 931 TVS scans performed in UKCTOCS between 2008 and 2011 with ovaries reported as 'seen and normal'. Software was developed to identify the exact images used by the sonographer to measure the ovaries. This was achieved by measuring caliper dimensions in the image and matching them to those recorded by the sonographer. A logistic regression classifier to determine visualization was trained and validated using ovarian dimensions and visualization data reported by the expert. RESULTS: The expert reviewer confirmed visualization of both ovaries (VR-Both) in 50.2% (502/1000) of the examinations. The software identified the measurement image in 534 exams, which were split 2:1:1 providing training, validation and test data. Classifier mean accuracy on validation data was 70.9% (95% CI, 70.0-71.8%). Analysis of test data (133 exams) provided a sensitivity of 90.5% (95% CI, 80.9-95.8%) and specificity of 47.5% (95% CI, 34.5-60.8%) in detecting expert confirmed visualization of both ovaries. CONCLUSIONS: Our results suggest that, in a significant proportion of TVS annual screens, the sonographers may have mistaken other structures for normal ovaries. It is uncertain whether or not this affected the sensitivity and stage at detection of ovarian cancer in the ultrasound arm of UKCTOCS, but we conclude that QC metrics based on self-reported visualization of normal ovaries are unreliable. The classifier shows some potential for addressing this problem, though further research is needed. © 2017 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Effect of diisopropanolamine upon choline uptake and phospholipid synthesis in Chinese hamster ovary cells.

Aminoalcohols differ in mammalian toxicity at least in part based upon their ability to alter the metabolism of phospholipids and to cause depletion of the essential nutrient choline in animals. This study examined the incorporation of diisopropanolamine (DIPA) into phospholipids (PLs) and effects of DIPA upon choline uptake and phospholipid synthesis in Chinese hamster ovary (CHO) cells. Results were compared to those of a related secondary alcohol amine, diethanolamine (DEA), whose systemic toxicity is closely associated with its metabolic incorporation into PLs and depletion of choline pools. DIPA caused a dose-related inhibition of (3)H-choline uptake by CHO cells that was approximately 3-4 fold less potent, based upon an IC50, than that reported for DEA. DIPA, in contrast to DEA, did not cause changes in the synthesis rates of (33)P-phosphatidylethanolamine, (33)P-phosphatidylcholine or (33)P-sphingomyelin at either non-toxic or moderately toxic concentrations. Only approximately 0.004%, of administered (14)C-DIPA was metabolically incorporated into PLs, over 30-fold less than the incorporation of (14)C-DEA under similar conditions. Overall, these data and previous pharmacokinetic and toxicity data obtained in vivo suggests that DIPA is distinct from DEA and lacks significant choline and PL metabolism related toxicity in animals.

Repeated dose toxicity and developmental toxicity of diisopropanolamine to rats.

The repeated dose oral and dermal toxicity of diisopropanolamine (DIPA) was evaluated in rats and compared to the reported toxicity of the related secondary alcohol amine, diethanolamine (DEA). Fischer 344/DuCrl rats were given up to 750 mg/kg/day by dermal application, 5 days/week, for 4 weeks; or up to 1,000 mg DIPA/kg/day by drinking water for 13 weeks to evaluate potential toxic effects. Time-mated female CRL:CD(SD) rats were given up to 1,000 mg/kg/day by gavage on gestation days (GD) 6-20 for evaluation of maternal and fetal effects. In the dermal toxicity study, no adverse treatment-related in-life effects other than mild irritation at the site of dermal application at >or= 500 mg/kg/day were observed. There were no systemic effects in rats given up to 750 mg/kg/day. In the subchronic oral toxicity study, the most significant effects were an increase in absolute and relative kidney weights, unaccompanied by histopathologic changes, at >or= 500 mg/kg/day DIPA. The latter effect was ameliorated following a 4-week recovery period. In the developmental toxicity study, there were no maternal or developmental effects at any dose level evaluated. The toxicity of DIPA contrasts with that of DEA which has been shown to affect a number of organ systems when repeatedly administered orally or dermally at similar or lower dosages.

Effect of strain and diet upon constitutive and chemically induced activities of several xenobiotic-metabolizing enzymes in rats.

The response of animals in toxicity studies reflects a complex interaction of a number of variables, some intrinsic to a particular study design and others resulting from the treatment itself. The influences of strain and diet upon constitutive and benzo(a)pyrene (B(a)P) induced activities of several hepatic Phase I and II enzymes were studied in a multifactoral design. Male and female CDF and Crl:CD rats were fed a standard rodent diet ad libitum, a 75% of ad libitum restricted feeding regimen or a phytoestrogen-free diet for approximately 3 weeks. During the last five days of the study, rats were administered either corn oil (vehicle) or 15 mg/kg/day B(a)P via oral gavage. The constitutive activities of hepatic CYP1A1, CYP1A2, CYP2B1/2, and mixed isoforms of UDP-glucuronosyl transferase, sulfotransferase, and glutathione-S-transferase varied significantly by feeding regimen and strain. Responses to B(a)P administration were also observed to be influenced by diet and strain in a manner similar to that observed for constitutive activities. These findings point out the potentially significant interactions of relatively commonly encountered variables that may affect results of hazard testing, especially when employing near metabolically saturating dosages of test chemicals.

Evaluation of the potential of triethanolamine to alter hepatic choline levels in female B6C3F1 mice.

Triethanolamine (TEA), a widely used nongenotoxic alcohol-amine, has recently been reported to cause an increased incidence of liver tumors in female B6C3F1 mice, but not in males nor in Fischer 344 rats. Choline deficiency induces liver cancer in rodents, and TEA could compete with choline uptake into tissues. The potential of TEA to cause choline deficiency in the liver of these mice as a mode of tumorigenesis was investigated. Groups of female B6C3F1 mice were administered 0 (vehicle) or a maximum tolerated dosage (MTD) of 1000 mg/kg/day TEA (Trial I) and 0, 10, 100, 300, or 1000 mg/kg/day TEA (Trial II) in acetone vehicle via skin painting 5 days/week for 3 weeks. Female CDF(R) rats were also administered 0 or an MTD dosage of 250 mg/kg/day TEA (Trial II) in a similar manner. No clinical signs of toxicity were noted, and upon sacrifice, levels of hepatic choline, its primary storage form, phosphocholine (PCho), and its primary oxidation product, betaine, were determined. A statistically significant decrease in PCho and betaine, was observed at the high dosage (26-42%) relative to controls and a dose-related, albeit variable, decrease was noted in PCho levels. Choline levels were also decreased 13-35% at the high dose level in mice. No changes in levels of choline or metabolites were noted in treated rats. A subsequent evaluation of the potential of TEA to inhibit the uptake of (3)H-choline by cultured Chinese Hamster Ovary Cells revealed a dose-related effect upon uptake. It was concluded that TEA may cause liver tumors in mice via a choline-depletion mode of action and that this effect is likely caused by the inhibition of choline uptake by cells.

Resonant excitation in a low-pressure linear ion trap.

It has been shown that through the process of resonant excitation the fragmentation of ions confined in a low-pressure (<0.05 mTorr) linear ion trap (LIT) can be accomplished while maintaining both high fragmentation efficiency and high resolution of excitation. The ion reserpine, 609.23 Da, has been fragmented with efficiencies greater than 90% while a higher mass ion, a homogeneously substituted triazatriphosphorine of mass 2721.89 Da, has been fragmented with 48% efficiency. This was accomplished by extended resonant excitation by low-amplitude auxiliary RF signals. Computer modelling of ion trajectories and analysis of the trapping potentials have demonstrated that a reduction in neutralization of ions on the rods (or losses on the rods) and increased fragmentation is a consequence of higher order terms in the potential introduced by the round-rod geometry of the LIT.

The pharmacokinetics of diethanolamine in Sprague-Dawley rats following intravenous administration.

In order to better understand the potential toxicity of diethanolamine (DEA) and preparatory to physiologically-based pharmacokinetic model development, the pharmacokinetics of DEA at high and low internal dose through 96-h post-dosing were determined in female Sprague-Dawley rats administered 10 or 100 mg/kg uniformly labeled 14C-DEA via intravenous injection. Clearance of DEA from blood was calculated to be approximately 84 ml/h/kg at the low dose, increasing to approximately 242 ml/h/kg at the high dose. The primary route of excretion of administered radioactivity, approximately 25-36%, was via the urine as parent compound. A majority of the administered radioactivity was recovered in the tissues of treated rats, especially in the liver and kidneys, suggesting a propensity of DEA or its metabolites for bioaccumulation. An accumulation of radioactivity also occurred gradually in the red blood cells from about 6-96 h post-dosing. Some evidence of dose dependency in the fate of iv-administered DEA was observed, suggesting that saturation of the bioaccumulation process(es) occurred at a dose level of 100 mg/kg.

Mammalian toxicity of 1,3-dichloropropene.

DCP has been utilized as a soil fumigant for more than 45 yr for the control for parasitic plant nematodes. Injected into soil before planting of crops, the instability of DCP in soil and water and its volatility dictate the principal route of human exposure that may occur, inhalation. Extensive data have been accumulated on the toxicity and metabolism of DCP. DCP is moderately toxic via oral or inhalation exposure, is irritating to the skin and eyes, and has potential to produce skin sensitization. It is rapidly and extensively metabolized. It has a half-life in the blood of rats and humans of only 3-7 min and < 10 min, respectively. Rats and mice excrete approximately 80% of even relatively high oral dosages within 24 hr, primarily as breakdown products of a glutathione conjugate or as carbon dioxide. These products reflect the primary routes of metabolism of DCP, via GSH-conjugative and hydrolytic pathways. An additional pathway based upon the epoxidation of DCP has also been proposed, but this does not appear to occur to any toxicologically significant degree in the presence of normally occurring GSTs. Direct evidence of the latter pathway is only been obtained at dosages of DCP in excess of the reported LD50. Humans also appear to rapidly metabolize DCP and excrete its metabolites. Subchronic toxicity studies of relatively pure DCP in rats and mice via oral or inhalation routes have resulted in portal-of-entry tissue effects that reflect the irritant properties of this chemical to nasal and gastric mucosa. At higher exposure levels in mice, however, toxicity was also identified in a remote tissue, the urinary bladder. Toxicity in dogs ingesting DCP was limited to the formation of a regenerative hypochromic, microcytic anemia. No teratological or reproductive effects were observed in rats or rabbits inhaling DCP vapors. Nonneoplastic changes from chronic dosing of DCP were generally similar to those observed in subchronic studies. Somewhat variable responses, however, have been observed for neoplastic effects, depending on the DCP formulation, route, and species used. Inhalation of a recent formulation increased the benign tumor incidence in the lungs of male mice (only) while ingestion of similar test material by rats and mice resulted in a low incidence of benign liver tumors in rats (only). In contrast, an older formulation containing Epi as a stabilizing agent administered to rats and mice via bolus oral dosing induced a number of malignant or benign tumors: in the forestomach and liver in rats and the forestomach, lung, and urinary bladder in mice. An equally complicated database has accumulated for DCP in vitro and in vivo genotoxicity testing. Genotoxicity has been reported in in vitro assays; however, confounding factors such as low-purity formulations, use of a genotoxic stabilizer, or generation of reactive impurities during attempts to purify test material have complicated interpretation. DCP appears to lack direct DNA reactivity, and a general trend toward decreasing activity with increasing complexity of the assay system and the presence of GST is evident. The weight-of-evidence evaluation of the genotoxicity data base suggests a lack of genotoxicity in vivo. Clearly definable treatment-related effects of DCP suggesting a plausible nongenotoxic mechanism of tumorigenic action, for example, enhanced cell proliferation, have not been in evidence in target tissues of treated animals. Thus, the specific mode of tumorigenesis of DCP in test animals remains to be elucidated but appears to involve a non-DNA-reactive mechanism. In conclusion, DCP-based soil fumigants have maintained an important role in agricultural despite the structural similarity of DCP to known genotoxic carcinogens and its own activity in in vitro genotoxicity assays. This role results from a combination of its use on soils before the planting of crops, its limited environmental half-life, rapid metabolism by animals via GSH conjugation and catabolism to CO2, lack of genotoxicity in in vivo assays, and an extensive toxicological database in animals, including several oncogenicity bioassays. These data, when combined with occupational and environmental exposure information, have provided a scientifically sound basis for the continued safe use of DCP-containing products.

Mechanistic aspects of the metabolism of 1,3-dichloropropene in rats and mice.

1,3-Dichloropropene (DCP) is used in agriculture for the control of nematodes in a variety of food crops. The major routes of metabolism for this halogenated aliphatic compound involve conjugation with glutathione and oxidation to carbon dioxide. An additional, minor route of metabolism proposed for this compound involves epoxidation to the corresponding 1,3-dichloropropene oxide (DCPO). Recent in vivo studies have provided evidence for the formation of DCPO in mice following intraperitoneal (ip) administration of 350-700 mg of DCP/kg, which is equal to, or exceeds, the reported oral LD(50) for this compound in mice [Schneider, M., et al. (1998) Chem. Res. Toxicol. 11, 1137-1144]. The potential for epoxidation of DCP in rats and mice at lower doses administered orally was therefore examined. Following oral administration of 100 mg of DCP/kg of body weight to F344 rats and B(6)C(3)F(1) mice, no DCPO was found in the liver or blood 0-90 min postdosing at a relatively low detection limit (10 ng/g of tissue). Only very low levels of DCPO were seen following ip administration of 100 mg of DCP/kg of body weight in blood of B(6)C(3)F(1) mice. Substantial levels of DCPO were only seen as a metabolite of DCP following ip administration of 700 mg of DCP/kg to B(6)C(3)F(1) or Swiss-Webster mice. Significant nonlinearity of DCP epoxidation was evident following ip administration, with approximately 130-fold less DCPO in mice given 100 vs 700 mg/kg. The time course of DCPO formation could only be followed for 76 min, due to 100% mortality in Swiss-Webster mice at the 700 mg/kg dose level. The formation of measurable DCPO in mice was also accompanied by acute hepatic damage following ip administration of 100 or 700 mg of DCP/kg to mice. In contrast, no evidence of acute toxicity was noted in mice treated with 100 mg/kg via oral gavage. These data suggest that measurable epoxidation of DCP to DCPO, in the rodent, occurs only at relatively high dose levels which result in acute hepatic injury or death. It was concluded that findings of DCPO formation at lethal doses administered via bolus internal injections do not reflect DCPO formation at lower doses administered via the natural portal of entry.

Absorption, distribution, metabolism and excretion of intravenously and dermally administered triethanolamine in mice.

Triethanolamine (TEA) is an amino alcohol having widespread applications in consumer goods and as an industrial chemical. A number of relatively high-dose dermal toxicity studies have been conducted in rats and mice reflecting the principal route of human exposure to TEA. The absorption, distribution, metabolism and excretion (ADME) of (14)C-TEA derived radioactivity were determined in male C3H/HeJ mice following dermal application of 2000 mg/kg (neat) or, to characterize blood kinetics, intravenous (iv) injection of 1 mg/kg (14)C-TEA. Balance and excretion data were also collected in mice utilizing several dermal dosing scenarios (1000 mg/kg in acetone, 2000 mg/kg neat, 2000 mg/kg in water) and, for comparative purposes, in male Fischer 344 rats dosed dermally with 1000 mg/kg neat (14)C-TEA. Urine, feces, expired CO(2) (iv) and, where appropriate, blood were collected over a 24- or 48-hour period post-dosing. The half-life for dermal absorption of radioactivity was estimated to be 1.3 hours. Intravenously administered radioactivity was eliminated in a biphasic manner with a prominent initial phase (half-life of 0.3 hr) followed by a slower terminal phase (half-life of 10 hr). Radioactivity was excreted primarily via the urine (49-69%) as unmetabolized TEA, regardless of dosage, route or vehicle used. Fecal excretion of radioactivity comprised 16-28% of dose administered. The body burden at sacrifice (sum of liver, kidney, carcass and non-application site skin) ranged from 3 to 6% of the dose. It was concluded that TEA is absorbed extensively following dermal application to mice at dosages relevant to toxicity testing and that acetone or water vehicles do not appear to significantly alter total uptake. Significantly, the blood kinetics and ADME of TEA in mice and/or rats differs from that of a related chemical, diethanolamine, which appears to be more toxic to rodents than TEA.

Chronic toxicity and oncogenicity studies of ingested 1, 3-dichloropropene in rats and mice.

Fischer 344 rats and B6C3F1 mice were administered 1, 3-dichloropropene (1,3-D) via their diets for up to 2 years, at dose levels of 0, 2.5, 12.5, or 25 mg 1,3-D/kg body wt/day for rats and 0, 2.5, 25, or 50 mg 1,3-D/kg body wt/day for mice. The test material was stabilized in the feed by microencapsulation in a starch/sucrose matrix (80/20%). Rats given 12.5 or 25 mg/kg/day, and mice given 25 or 50 mg/kg/day, had decreased body weights and body weight gains. There were no effects on survival or clinical pathology parameters for rats or mice. Histopathologic effects attributed to treatment in rats consisted of basal cell hyperplasia of the nonglandular mucosa of the stomach in males and females given 12.5 or 25 mg/kg/day for 12 and 24 months and an increased number of hepatocellular adenomas in males given 12.5 or 25 mg/kg/day and females given 25 mg/kg/day for 24 months. The increase in hepatocellular adenomas was statistically identified by pairwise comparison only in males given 25 mg/kg/day. An increased incidence of eosinophilic foci of altered cells in the liver was also noted in all treated groups of rats at 24 months. The latter observation, however, was considered of equivocal toxicological significance because of the common spontaneous occurrence of liver foci in aged Fischer 344 rats. The only histologic change attributed to treatment in mice was decreased size of hepatocytes in males given 50 mg/kg/day for 12 months. The decreased size of hepatocytes was consistent with decreased cytoplasmic glycogen content and corresponded to decreased liver weights. This effect was not present at 24 months. There was no oncogenic response observed in mice. The low-dose level of 2.5 mg/kg/day was interpreted as the no-observed-adverse-effect level (NOAEL) for systemic chronic toxicity of 1,3-D in the Fischer 344 rat. The no-observed-effect level (NOEL) for chronic systemic toxicity was 2.5 mg/kg/day in the B6C3F1 mouse.

Potential mechanisms of tumorigenic action of diethanolamine in mice.

Diethanolamine (DEA), a secondary amine found in a number of consumer products, reportedly induces liver tumors in mice. In an attempt to define the tumorigenic mechanism of DEA, N-nitrosodiethanolamine (NDELA) formation in vivo and development of choline deficiency were examined in mice. DEA was administered with or without supplemental sodium nitrite to B6C3F1 mice via dermal application (with or without access to the application site) or via oral gavage for 2 weeks. Blood levels of DEA reflected the dosing method used; oral greater than dermal with access greater than dermal without access. No NDELA was observed in the urine, blood or gastric contents of any group of treated mice. Choline, phosphocholine and glycerophosphocholine were decreased

Subchronic and chronic toxicity of ingested 1,3-dichloropropene in dogs.

The potential toxicologic effects to dogs of 1,3-dichloropropene (1, 3-D), a soil fumigant used for the control of nematodes, were investigated. The 13-week subchronic toxicity study consisted of male and female beagle dogs (4/sex/dose group) given approximately 0, 5, 15, or 41 mg 1,3-D/kg body wt/day (approximately equivalent amounts of cis and trans isomers) via their diets. The 1-year chronic toxicity study consisted of male and female beagle dogs (4/sex/dose group) provided diets delivering approximately 0, 0.5, 2. 5, or 15 mg/kg body wt/day. The test material was stabilized in the feed by microencapsulation in a starch/sucrose matrix (80/20). In both the 13-week and the 1-year studies, the primary effect of 1,3-D in male and female dogs ingesting a dosage of >/=15 mg/kg/day was hypochromic, microcytic anemia. The anemia was regenerative, with increased erythropoietic activity characterized by polychromasia of erythrocytes and increased numbers of reticulocytes in peripheral blood. In the 13-week study, the anemia in dogs given 41 mg/kg/day progressively worsened over time, while the anemia in dogs given 15 mg/kg/day remained relatively constant between 42 and 90 days of dosing. Partial reversal of the anemia of high-dose animals occurred during a 5-week recovery period following the 13-week dosing regimen. In the 13-week study, terminal fasted body weights of males given 15 or 41 mg/kg/day were decreased 3 and 28%, respectively, and body weights of females given 5, 15, or 41 mg/kg/day were decreased 4.5, 12, and 24%, respectively, relative to controls. Males given 5 mg/kg/day for 13 weeks had no change in body weights relative to controls. In the 1-year study, the hypochromic microcytic anemia in dogs given 15 mg/kg/day remained relatively constant in severity between 3 and 12 months of treatment. Histopathologic alterations associated with anemia in the 1-year study consisted of increased hematopoiesis of the bone marrow and increased extramedullary hematopoiesis of the spleen. Body weights of males given 15 mg/kg/day were 5-12% lower than controls during the first 13 weeks of the study and 13-19% lower than controls during the remaining 9 months. Body weights of females given 15 mg/kg/day were 5-14% lower than controls over the majority of the dosing period. Males and females given 0.5 or 2.5 mg/kg/day for 1 year had no change in body weights relative to controls. A no-observed-effect level of 2.5 mg/kg/day was established for male and female dogs from the 1-year study.

Hepatic lacI and cII mutation in transgenic (lambdaLIZ) rats treated with dimethylnitrosamine.

The recent introduction of a transgenic rat in vivo mutation assay is a much needed supplement to the transgenic mouse models and offers the tools necessary for collecting target tissue specific genotoxicity data in this species. The utility of the Big Blue(R) rat for the detection of in vivo mutations was investigated by studying spontaneous and dimethylnitrosamine (DMN)-induced hepatic mutations. High molecular weight DNA isolated from Big Blue(R) rat livers typically yielded good transgene rescue efficiency of up to 5x105 plaque forming units per packaging reaction. DMN, when administered by oral gavage at dose levels of 0.2, 0.6, 2.0, and 6.0 mg kg-1 day-1, induced up to a 4.5-fold increase in mutations at the highest dose level. There was no apparent difference between the lacI vs. cII target genes of the shuttle vector in either the background or DMN-induced mutant frequencies. These results suggest that the transgenic rat model is a useful tool for studying potential genotoxicity in target organs and, with further validation, the selectable cII target could be an attractive alternative to the conventional lacI color screening method for the detection of mutations in the lambdaLIZ shuttle vector.

Bioavailability and pharmacokinetics of microencapsulated 1,3-dichloropropene in rats.

The potential oral toxicity of 1,3-dichloropropene (1,3-D) has been evaluated in a number of dietary toxicity studies. The relatively high vapor pressure of 1,3-D, its short half-life in drinking water, and its reactivity with constituents of feed necessitated the use of a microencapsulated formulation (starch-sucrose shell) of 1,3-D in these studies. The bioavailability of ingested microencapsulated 1,3-D was determined by characterizing and comparing the kinetics of 1,3-D in the blood of female F344 rats coadministered microencapsulated 1,3-D and neat 13C-1,3-D (25 mg/kg each) via gavage. Blood concentrations of total or cis- and trans-isomers of 1,3-D in treated rats were determined using gas chromatography-mass spectroscopy (GC-MS) or in situ membrane extraction MS. Urine was also collected and analyzed by GC-MS for the presence of the mercapturate excretion product of 1,3-D [N-acetyl-S-(3-chloropropenyl-2)-L-cysteine; 1,3-DMA]. Blood levels of 1,3-D and 13C-1,3-D displayed similar kinetics, peaking within 10 min of dosing followed by a rapid biphasic elimination. Higher peak blood levels and greater blood curve areas (AUC) were attained for trans- than cis-1,3-D and 13C-1,3-D and greater amounts of cis- than trans-1,3-DMA and 13C-1,3-DMA were excreted in the urine consistent with the known rapid and disproportionate glutathione conjugation of the cis-isomer in the gastric mucosa. Slightly higher cis-1,3-D than cis-13C-1,3-D blood levels and AUCs were also consistently noted while the reverse was true for urinary excretion of cis-13C-1,3-DMA and cis-1,3-DMA suggesting that 1,3-D derived from microencapsulated test material may be absorbed and/or metabolized in the stomach mucosa at a slightly slower rate than that from neat material. The latter, however, would be of no consequence during the administration of 1,3-D to animals via their diets as competing test materials would not be present and 1,3-D blood kinetics were unaffected. Overall, the results of this study demonstrate the ready bioavailability of microencapsulated 1,3-D and rapid elimination of 1,3-D from the blood of rats.

Mode of action considerations in the use of transgenic animals for mutagenicity and carcinogenicity evaluations.

Genetically altered rodent models can be useful in facilitating the extrapolation of results from animal carcinogenicity studies to human risk assessment by contributing mode of action data. Transgenic mutation models make it possible to analyze mutations in vivo in any tissue of interest. Validation studies using genotoxic and epigenetic carcinogens indicated a good correlation between mutation induction and the tumor target tissues and have provided data on mode of tumorigenic action. However, carcinogenesis is a complex process and mutation induction in a given tissue does not always lead to tumors in that tissue. Genetically altered animal models such as the p53 +/- mouse can be useful in differentiating genotoxic carcinogens from those operating by non-genotoxic mechanisms. An understanding of the tumor responses of these short-term alternative transgenic and knockout mice to epigenetic events such as tissue injury and enzyme induction at high maximum tolerated doses will eventually increase our level of confidence in these animal models for hazard evaluation and mechanistic studies.

Evaluation of a novel assay of potential toxicity/neurotoxicity of carpet emissions (VOCs) in mice.

A private testing laboratory utilizing the whole-body plethysmograph/head-only exposure apparatus outlined in the respiratory irritation assay ASTM E981-84, along with a novel exposure regimen, has reported neurotoxic effects and mortality in mice exposed to relatively low levels of volatile organic compounds (VOCs) emitted from a number of consumer products. This methodology was evaluated by exposing groups of mice, including unrestrained and sham-treated animals, to VOCs generated from a sample of carpet reported to be neurotoxic using the modified assay. General toxicological (haematological measurements, organ weights, gross pathology, histopathology) and specific neurotoxicity (functional observations, body temperature, histopathology of nervous tissues) parameters were evaluated. No effects related to exposure to carpet VOCs were observed in the mice. However, despite careful handling, a number of effects were observed which were attributed to the repeated restraint of mice in the ASTM E981 apparatus. These included a number of minor physical injuries, decreased body weights, altered thymus weights, compression damage to the liver and haemorrhage of the pituitary gland. It was concluded that the modification of the original ASTM E981 methodology may result in physical injuries and stress which may significantly affect any evaluation of toxicity and neurotoxicity in treated animals and result in inaccurate conclusions.

Toxicology of mono-, di-, and triethanolamine.

The chemistry, biochemistry, toxicity, and industrial use of monoethanolamine (MEA), diethanolamine (DEA), and triethanolamine (TEA) are reviewed. The dual function groups, amino and hydroxyl, make them useful in cutting fluids and as intermediates in the production of surfactants, soaps, salts, corrosion control inhibitors, and in pharmaceutical and miscellaneous applications. In 1995, the annual U.S. production capacity for ethanolamines was 447,727 metric tons. The principal route of exposure is through skin, with some exposure occurring by inhalation of vapor and aerosols. MEA, DEA, and TEA in water penetrate rat skin at the rate of 2.9 x 10(-3), 4.36 x 10(-3) and 18 x 10(-3) cm/hr, respectively. MEA, DEA, and TEA are water-soluble ammonia derivatives, with pHs of 9-11 in water and pHa values of 9.3, 8.8, and 7.7, respectively. They are irritating to the skin, eyes, and respiratory tract, with MEA being the worst irritant, followed by DEA and TEA. The acute oral LD50s are 2.74 g/kg for MEA, 1.82 g/kg for DEA, and 2.34 g/kg for TEA (of bw), with most deaths occurring within 4 d of administration. MEA is present in nature as a nitrogenous base in phospholipids. These lipids, composed of glycerol, two fatty acid esters, phosphoric acid, and MEA, are the building blocks of biomembranes in animals. MEA is methylated to form choline, another important nitrogenous base in phospholipids and an essential vitamin. The rat dietary choline requirement is 10 mg kg-1 d-1; 30-d oral administration of MEA (160-2670 mg kg-1 d-1) to rats produced "altered" liver and kidney weights in animals ingesting 640 mg kg-1 d-1 or greater. Death occurred at dosages of 1280 mg kg-1 d-1. No treatment-related effects were noted in dogs administered as much as 22 mg kg-1 d-1 for 2 yr. DEA is not metabolized or readily eliminated from the liver or kidneys. At high tissue concentrations, DEA substitutes for MEA in phospholipids and is methylated to form phospholipids composed of N-methyl and N, N-dimethyl DEA. Dietary intake of DEA by rats for 13 wk at levels greater than 90 mg kg-1 d-1 resulted in degenerative changes in renal tubular epithelial cells and fatty degeneration of the liver. Similar effects were noted in drinking water studies. The findings are believed to be due to alterations in the structure and function of biomembranes brought about by the incorporation of DEA and methylated DEA in headgroups. TEA is not metabolized in the liver or incorporated into phospholipids. TEA, however, is readily eliminated in urine. Repeated oral administration to rats (7 d/wk, 24 wk) at dose levels up to and including 1600 mg kg-1 d-1 produced histopathological changes restricted to kidney and liver. Lesions in the liver consisted of cloudy swelling and occasional fatty changes, while cloudy swelling of the convoluted tubules and loop of Henle were observed in kidneys. Chronic administration (2 yr) of TEA in drinking water (0, 1%, or 2% w/v; 525 and 1100 mg kg-1 d-1 in males and 910 and 1970 mg kg-1 d-1 in females) depressed body and kidney weights in F-344 rats. Histopathological findings consisted of an "acceleration of so-called chronic nephropathy" commonly found in the kidneys of aging F-344 rats. In B6C3F1 mice, chronic administration of TEA in drinking water (0, 1%, or 2%) produced no significant change in terminal body weights between treated and control animals or gross pathological changes. TEA was not considered to be carcinogenic. Systemic effects in rats chronically administered TEA dermally (0, 32, 64, or 125 mg kg-1 d-1 in males; 0, 63, 125, or 250 mg kg-1 d-1 in females) 5 d/wk for 2 yr were primarily limited to hyperplasia of renal tubular epithelium and small microscopic adenomas. In a companion mouse dermal study, the most significant change was associated with nonneoplastic changes in livers of male mice consistent with chronic bacterial hepatitis.